Jean-Louis Mandel

Neurodevelopmental disorders (NDDs) with a genetic basis are frequently associated with neurological and sensory impairments; yet vestibular symptoms remain underrecognized. Vertigo, dizziness, and imbalance can significantly impact daily functioning, but their prevalence and genetic associations in individuals with NDDs are poorly understood. This study aimed to assess the occurrence of vestibular symptoms in individuals with genetic NDDs. We conducted an international, prospective cross-sectional study using data from the GenIDA database, which includes individuals with confirmed genetic disorders, intellectual developmental disorders and/or other NDDs. Caregivers completed a survey assessing the occurrence of vertigo, dizziness, and balance issues, as well as emotional distress, psychiatric comorbidities, and associated conditions such as migraine and epilepsy. We analyzed the prevalence of vertigo in the past 12 months and explored potential genetic contributors. The occurrence rate of vertigo (11.8%) and imbalance (27.7%) in the past 12 months was dramatically increased in individuals with genetic NDDs compared to that observed in the general population. However, less than 40% of patients had received a formal diagnosis for their vertigo. Notably, vertigo was significantly associated with an increased likelihood of feeling unhappy and depressed. Twenty genetic anomalies causally involved in NDDs were identified as potential contributors to vertigo, including 22q11.2 microdeletions and variants in ANKRD11, MED13L, PACS1 and SHANK3. Vertigo appears highly prevalent, yet underdiagnosed, in individuals with genetic NDDs. The identified genetic anomalies suggest that (1) vertigo may be an intrinsic component of NDDs, reflecting shared genetic pathways leading to inner ear malformations, vestibular network dysfunction, cerebellar abnormalities, and epilepsy, alongside other neurodevelopmental features; and/or (2) early vestibular dysfunction may exacerbate neurodevelopmental impairments.

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5′ splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5′ splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69–24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months–24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.

Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD (CELF2, APC2, etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B, an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1-KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.

The Koolen‐de Vries syndrome (KdVS) is a multisystem disorder characterized by developmental delay, intellectual disability, characteristic facial features, epilepsy, cardiovascular and urogenital malformations, and various musculoskeletal disorders. Scoliosis is a common feature. The aim of this study is to fill the gap in the current knowledge about scoliosis in individuals with KdVS and to provide recommendations for management and follow‐up. In total, 54 individuals with KdVS were included in the study, with a mean age of 13.6 years (range 1.9–38.8 years). Spine radiographs, MR scans, and corresponding radiology reports were analyzed retrospectively for scoliosis and additional anomalies. The presence of scoliosis‐related clinical conditions was assessed in participants' medical records and by use of a parent survey. Scoliosis was present in 56% of the participants (30/54) with a mean age of onset of 10.6 years and curve progression during the growth spurt. Prevalence at age 6, 10, and 18 years was, respectively, 9%, 41%, and 65%. Most participants were diagnosed with a single curve (13/24, 54%), of which five participants had a long C‐curve type scoliosis. No significant risk factors for development of scoliosis could be identified. Severity was mostly classified as mild, although 29% (7/24) of the curves were larger than 30° at last follow‐up. Bracing therapy was received in 13% (7/54), and surgical spinal fusion was warranted in 6% (3/54). Remarkably, participants with scoliosis received less often physical therapy compared to participants without scoliosis (P = 0.002). Scoliosis in individuals with KdVS should be closely monitored and radiologic screening for scoliosis and vertebrae abnormalities is recommended at diagnosis of KdVS, and the age of 10 and 18 years.

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1 ‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1 ‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.